Thiazolo (3,4-a) benzimidazoles and derivatives thereof

ABSTRACT

1-Imino-1H,3H-thiazolo(3,4-a)benzimidazoles and 1H,3Hthiazolo(3,4-a)benzimidazole-3-ones are provided which are useful as parasiticides and rodenticides.

United States Patent Haugwitz et al.

[ 51 May 23, 1972 [54] THIAZOLO [3,4-A] BENZHVIIDAZOLES AND DERIVATIVESTHEREOF [72] Inventors: Rudiger D. Haugwitz, Highland Park; VenkatachalaLakshmi Narayanan, North Brunswick, both of NJ.

[73] Assignee: E. R. Squibb & Sons, Inc., Princeton, NJ.

221 Filed: May 4, 1970 [21] Appl. No.: 34,552

[52] U.S. Cl ..260/306.7, 260/309.2, 424/200, 424/270 [51] InLCl...C07d99/06 [58] HeldofSearch... ..260/306.7

[ ABSTRACT l-lminol H,3H-thiazolo[ 3 ,4-a]benzimidazoles and l H,3H-thiazolo[3,4-a]benzimidazole 3-ones are provided which are useful asparasiticides and rodenticides.

7 Claims, No Drawings 3,665,007 1 2 THIAZOLO [3,4-A] BENZIMIDAZOLES AND6. CH; CH:

DERIVATIVES THEREOF This invention relates to the synthesis of a novelheterocyclic system; more specifically, it relates tol-in1ino-ll-l,3l-lthiazolo[3,4-a]benzimidazoles andlH,3l-l-thiazolo[3,4- 5 albenzimidazole-S-ones of the structure J=NE i ix 6. (R)n wherein t R can be hydrogen, hydroxy, halo, nitro, loweralkyl, aryl lower alkyl, lower alkoxy, cyano, mercapto, thiocyano, Namino, substituted amino, aryl, lower alkyl aryl; NC- R is lower alkyi,aryl lower alkyl, aryl, lower alkyl aryl or i J hydrogen; X is NH oroxygen; and n is l or 2. CH3 The lower alkyl groups represented by thesymbols R and R N are straight or branched chain aliphatic hydrocarbonradicals CHKO 5 having up to seven carbon atoms, such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, heptyl, NH andthe like. The lower alkyl groups can include as substituents any of thearyl groups mentioned below. 04H

With respect to R, the lower alkoxy groups represented I thereby includestraight and branched chain radicals of up to seven carbon atoms,corresponding to the above alkyl groups, e.g., methoxy, ethoxy, propoxy,isopropoxy, and the like. In addition, the term lower alkoxy includeslower alkylenedioxy groups wherein lower alkylene includes bivalentradicals of the kind mentioned above with respect to lower alkyl, suchas HS S methylenedioxy and ethylenedioxy. R can include each of the Ifour halogens but chlorine and bromine are preferred. The N NHsubstituted amino groups include monoor di-lower alkylamino whereinlower alkyl is as defined above, such as H3CO methylamino, ethylamino,isopropylamino, heptylamino, s dirnethylamino, diethylarnino,methylethylamino, methylbu- 40 J tylamino, ethyl i-propylamino and thelike.

The term aryl includes monocyclic or bicyclic monovalent or bivalentaromatic ring systems such as phenyl or naphthyl, hem and naphtho. Thesearyl radicals can inelude as substituents any of the lower alkyl groupsincluded S within the definition of R and R. Br N =0 It is to beunderstood that where more than one R sub stituent is present, each Rmay be the same or different.

Preferred are those compounds wherein R and R are CZHS hydrogen,XisNHorQandn is 1. No

Exemplary of compounds falling within the present inven- I 5 tionInclude the following: N :0 1. N (\S 12. 01 C411, N =NH JiNJfl NC S N18. H S N (\s N Lo 19. I /N\\ S 20. H O /N\ S N LO Compounds of formulaI, where X is oxygen, are conveniently prepared from tricyclic compoundsof formula I, where X is NH, in accordance with the following reaction:

As indicated, the conversion is carried out in the presence of an acid.Dilute or concentrated aqueous acids such as any of the halogen acids,sulfuric acid, nitric acid, and/or phosphoric acid can be utilized.Preferred is hydrochloric acid. The conversion can be carried out atambient temperature, although temperatures up to C. can be employed. Theconversion can be carried out in several minutes up to a period ofseveral hours, depending upon the concentration of the acid and thetemperature employed. The acid can be employed in a molar ratio tobenzimidazoles of the formula I where X is NH of within the range offrom about 800:1 to about 2:1 and preferably from about 650:1 to about400:1.

Compounds of formula I where X is NH can be prepared by forming athiocyanic acid ester of a benzimidazole of the wherein R, R and n areas defined hereinbefore, and then cyclizing the thiocyanic acid ester toform the tricyclic compounds of the invention (where X is NH).Intramolecular cyclization to form the tricyclic compounds of theinvention is carried out by dissolving the thiocyanic acid ester (II) ina protic solvent, for example, a monohydric or polyhydric alcoholcontaining up to about five carbon atoms, such as methanol, ethanol,isoamyl alcohol or glycerol, or an aprotic solvent, such as dirnethylsulfoxide, dimethyl formamide, acetonitrile, ethyl acetate or diglyme,and heating the resulting solution at elevated temperatures ranging fromabout 35 to about for periods ranging from 1 to 24 hours.

Alternatively, tricyclic ring-structures of formula I where X is NI-Ican be synthesized directly from 2-halomethyl benzimidazoles (III) andthiocyanic acid salts in suitable solvents at elevated temperatures:

where R and R are as defined earlier, Y=Cl, Br, or I, and M is an alkalimetal such as sodium, potassium or lithium, an alkaline earth metal suchas calcium, barium or magnesium, or ammonium. Protic or aprotic solventssuch as stated previously, can be advantageously employed attemperatures ranging from about 35 to about I00", for periods of about10 minutes to several hours.

The thiocyanic acid salts are employed in a molar ratio to the2-halomethyl benzimidazoles (III) of within the range from about 1:1 toabout l0:l and preferably from about 1:1 to about 4: l

The thiocyanic acid esters of benzimidazoles (II) can be prepared asdescribed in U. S. application Ser. No. 17,320,

filed Mar. 6,1970, the disclosure of which is incorporated herein byreference.

The compounds of formula 1 form physiologically acceptable acid-additionsalts with inorganic and organic acids. These acid-addition saltsfrequently provide useful means for isolating the products from reactionmixtures by forming the salt in a medium in which it is insoluble. Thefree base may then be obtained by neutralization, e.g., with a base suchas sodium hydroxide. Then any other salt may again be formed from thefree base and the appropriate inorganic or organic acid. Illustrativeare the hydro-halides, especially the hydrochloride and hydrobromidewhich are preferred, sulfate, nitrate, phosphate, oxalate, tartrate,maleate, fumarate, pamoate, citrate, succinate, benzoate, ascorbate,methanesulfonate, benzenesulfonate, toluenesulfonate, and the like.

The compounds of this invention can be utilized as parasiticides androdenticides, being particularly useful against Crithidia fasciculata.These compounds when utilized as parasiticides form the activeingredient in feed stuffs for cattle, hogs and chickens, being admixedwith said feed stock in from 0.1 to 25 mg. per 100 kg weight of feedstuffs with the most preferred range being from about 5 to mg. per 100kg. of feed stuffs.

As anti-inflammatory agents, the compounds of this invention may be usedtopically in lieu of and in the same manner as cortisone in thetreatment of acute inflammatory and allergic conditions of the eye, skinor mucosa, e.g., as suspension, ointment or cream containing about 0.1to about 2.5 percent by weight, of a compound of formula 1 orphysiologically acceptable salt thereof. In the rabbit or cow, forexample, a 1 percent ointment is applied to the skin area 3 to 4 timesdaily.

The following Examples, in the opinion of the inventors, representpreferred embodiments of their invention:

EXAMPLE 1 1-lminol H,3 H-thiazolo[ 3,4-a1benzimidazole A mixture of 34g. of 2-chloromethyl-benzimidazole, and 60 g. of ammonium thiocyanate in1,000 ml. of methanol, is refluxed for one hour. The solution isevaporated to about half its volume and then chilled.

The product separates and is filtered off. Recrystallization frommethanol yields 8.3 g. of pure product, m.p. l69-l70.

Anal. calcd for C,H,N S: C, 57.12; H, 3.73

Found: C, 57.23; H, 3.96;

EXAMPLE 2 (a) Thiocyanic acid, 2-benzimidazoyl methyl ester A solutionof 8.4 g. of ammonium thiocyanate in 68 m1. of dimethyl sulfoxide, istreated with 9 g. of 2-chloromethylbenzimidazole, and the clear solutionis stirred for about hours at about ambient temperatures. Water is thenadded until no further precipitate forms. The solid is filtered, washedwith water, dissolved in dimethyl sulfoxide and reprecipitated withwater. This reprecipitating process is repeated; upon drying at 25 C.under a vacuum of 0.01 mm/Hg, 4.2 g. of pure ester is obtained, m.p.154-155.

Anal. Calcd for C H N S: C, 57.20; H, 3.73;

Found: C, 57.10; H, 3.86;

(b) l1mino-1H,3H-t.hiazolo[3 ,4-a]benzimidazole A solution of 4.2 g. ofthiocyanic acid, 2-benzimidazoyl methyl ester in 200 ml. of methanol isrefluxed for one hour; cooling and water addition, until completeprecipiatation is achieved furnishes 2 g. ofl-imino-lH,3H-thiazolo[3,4-a] benzimidazole.

EXAMPLE 3 1H,3H-Thiazolo[ 3,4-a1benzimidazole-3-one To 195 ml. of hotconcentrated hydrochloric acid there is added 7.8 g. of1-imino-lH,3H-thiazo1o-[3,4-a] benzimidazole. This mixture is stirred ona steam bath for 10 minutes. Then, the resulting solution is cooled andbrought to pH 5 with concentrated ammonia. The formed precipitate isfiltered and crystallized twice from ethyl acetate to yield 2.8 g. pureproduct, m.p. 2 l 2-2 14.

Anal. Calc'd. for c,H,N,0s; c, 56.85; H, 3.18;

N, 14.73 Found: C, 56.99; H, 3.34;

EXAMPLE 4 6Chloro-1-imino-lH,3l-l-thiazolo[3,4-a]benzimidazole A mixtureof 10 g. of 2-chloromethyl-5-ch1orobenzimidazole and 8 g. of ammoniumthiocyanate is dissolved in 200 ml. of dimethyl formamide and heated for3.5 hours at 50. Water is added until no further precipitate is formed.This mixture is allowed to stand overnight at room temperature; then theformed precipitate is crystallized twice from ethyl ether to yield 6 g.of pure product, m.p. 156-l58.

Anal. Calcd for C H ClN S: C, 48.33; H, 2.70;

Found:

EXAMPLE 5 Anal. Calcd: C, 59.09; H, 4.47; N, 20.67 Found: C, 59.25; H,4.46; N, 20.46.

EXAMPLE 6 1-Imino-3-phenyl-lH,3H-thiazolo[3,4-a1benzimidazole Utilizingthe procedure of Example 1, but substitutingaphenyl-2-bromomethyl-benzimidazole for 2-chloromethylbenzimidazole, theproduct recovered is l-imino-3-phenyl-lH,3H-thiazolo[3,4-a1benzimidazole.

EXAMPLE 7 1-Imino-6,7-dimethyl-1H,3H-thiazolo[3,4-a]benzimidazoleUtilizing the procedure of Example 1, but substituting 5,6-dimethyl-2-chloromethyl-benzimidazole for 2-chloromethy1- benzimidazole,the product recovered is l-imino-6,7- dimethyl- 1 H,3H-thiazolo[ 3,4-a1benzimidazole.

EXAMPLES 8 to 13 Following the procedure of Example 1, but utilizing thecompounds illustrated in Column A of Table l in lieu of 2-chloromethyl-benzimidazole and ammonium thiocyanate, the product formedhas the structure of Column B:

EXAMPLES 14 to 18 Following the procedure of Example 3, but utilizingthe compounds illustrated in Column A of Table H in lieu of l- 3. Acompound in accordance with claim 1, wherein X is 4. A compound inaccordance with claim 1, wherein X is 0. 5. A process for preparingcompounds as defined in acimino-ll-l,3H-thiazolo[3,4-a]benzimidazole andthe acid, the cordance with claim 1 wherein X is NH, which comprisesproduct formed has the structure of Column B.

forming a solution of a compoundof the structure TABLE II BenzirnidazoleBenzimidazol-one R! ?I I (\i /NYX J a s Cu CH3 CH3 CzH 02H! CQH5CH2 H015-CN CoHsCHz H HI B-(CHahN- We claim: L Compounds of the formula N l vSCN 6o (Rn) 1 IH (R),, wherein R, R and n are as defined in Claim 1, ina profic solvent or an aprotic solvent, heating the resulting solutionat a wherein R is selected from the group consisting of hydrogen, loweralkyl, aryl lower alkyl, lower alkoxy, lower alkylenedioxy, halo, nitro,hydroxy, amino, monoor di-lower temperature within the range of fromabout 35 to about 165 C. to form a benzirnidazole as defined in claim 1.

6. A process for preparing compounds in accordance with alkylamino,cyano, thiocyano, mercopto, phenyl lower alkyl, claim 1, wherein X isNH, which comprises reacting a 2- naphthyl, naphthyl lower alkyl,wherein phenyl and naphthyl halomethyl benzimidazole of the structureare optionally substituted by lower alkyl, and hen: or naphtho,optionally substituted by lower alkyl, R is selected from the groupconsisting of hydrogen, lower alkyl, phenyl, naphthyl, phenyl loweralkyl, naphthyl lower alkyl, lower alkyl phenyl, and lower alkylnaphthyl, X is NH or oxygen and n is l or 2.

2. A compound in accordance with claim 1, wherein R and R are hydrogenand X is NH.

wherein R, n and R are as defined in claim 1, and Y is Cl, Brtemperature up to about 100 C. to form a compound of the or I, with thethiocyanic acid salt of the structure structure MSCN wherein M is analkali metal, alkaline earth metal or ammonium, at a temperature withinthe range of from about 35 to about 100 C.

7. A process for preparing a benzimidazol-one in ac- J cordance withclaim 1, which comprises mixing a (Rh benzimidazole as defined in claim1 with an aqueous inorganic acid at a temperature within the range offrom about ambient wherein R, n and R are as defined in claim 1.

Page 1 of 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PatentNo. 665,007 Dated May 23, 1972 Inventor(s) Rudiger D. Haugwitz et al.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column formula that portion of the formula reading C I-I C 'H N N 5should be I Y S l N L N l=- Column 7, Table I, Example 11, under thecolumn M+, "NH should read -NH Column 7, claim 1, in the formula,

, should be CERTIFICATE OF CORRECTION Patent No. 3, 665,007 Dated ay1972 InVentOr($) Rudiger D. Hauqyritz et a1.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 8, claim 5, in the formula Column 8, claim 6, in the formula N SN should be Y UNITED STATES PATENT OFFICE Page 3 of 3 CERTIFICATE OFCORRECTION Patent No. 3,665,007 Dated May 23, 1972 Invent0r(s) RudigerD. Hauqwitz et a1.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 10, claim 7, in the formula RI fi s N\ N l X should be N 1.. O

Column 7, claim 1, line 67 "mercopto, phenyl lower alkyl" should read--mercapto, phenvl, phenyl lower alkyl-- Signed and Sealzd thisThirteenth D3) of June 1978 [SEAL] Arrest:

DONALD W. BANNER RUTH C. MASON Attesting Ojficer Commissioner of Patentsand Trademarks

2. A compound in accordance with claim 1, wherein R and R'' are hydrogenand X is NH.
 3. A compound in accordance with claim 1, wherein X is NH.4. A compound in accordance with claim 1, wherein X is
 0. 5. A processfor preparing compounds as defined in accordance with claim 1 wherein Xis NH, which comprises forming a solution of a compound of the structure6. A process for preparing compounds in accordance with claim 1, whereinX is NH, which comprises reacting a 2-halomethyl benzimidazole of thestructure
 7. A process for preparing a benzimidazol-one in accordancewith claim 1, which comprises mixing a benzimidazole as defined in claim1 with an aqueous inorganic acid at a temperature within the range offrom about ambient temperature up to about 100* C. to form a compound ofthe structure